The present invention relates to inhibitors of fatty acid hydrolase. More particularly, the invention relates to inhibitors of fatty acid hydrolase employing a heterocyclic pharmacophore.
Fatty acid amide hydrolase (FAAH), referred to as oleamide hydrolase and anandamide amidohydrolase in early studies, is an integral membrane protein that degrades fatty acid primary amides and ethanolamides including oleamide and anandamide, as illustrated in FIG. 1 (M. P. Patricelli, et al., (1998) Biochemistry 37, 15177-15187.D. G. Deutsch, et al., (1993) Biochem. Pharmacol. 46, 791-796; F. Desarnaud, et al., (1995) J. Biol. Chem. 270, 6030-6035; C. J. Hillard, et al., (1995) Biochim. Biophys. Acta 1257, 249-256; N. Ueda, et al., (1995) J. Biol. Chem. 270, 23823-23827; R. L. Omeir, et al., (1995) Life Sci. 56, 1999-2005; S. Maurelli, et al., (1995) FEBS Lett. 377, 82-86; and M. Maccarrone, et al., (1998). J. Biol. Chem. 273, 32332-32339). The distribution of FAAH in the CNS suggests that it degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation (E. A. Thomas, et al., (1997) J. Neurosci. Res. 50, 1047-1052). FAAH hydrolyzes a wide range of oleyl and arachidonyl amides, the CB1 agonist 2-arachidonylglycerol, the related 1-arachidonylglycerol and 1-oleylglycerol, and methyl arachidonate, illustrating a range of bioactive fatty acid amide or ester substrates. (W. Lang, et al., (1999) J. Med. Chem. 42, 896-902; S. K. Goparaju, et al., (1998) FEBS Lett. 442, 69-73; Y. Kurahashi, et al., (1997) Biochem. Biophys. Res. Commun. 237, 512-515; and T. Bisogno, et al., (1997) Biochem. J. 322, 671. Di Marzo, V., T. Bisogno, et al., (1998) Biochem. J. 331, 15-19). Although a range of fatty acid primary amides are hydrolyzed by the enzyme, FAAH appears to work most effectively on arachidonyl and oleyl substrates (B. F. Cravatt, et al., (1996) Nature 384, 83-87; and D. K. Giang, et al., (1997) Proc. Natl. Acad. Sci. USA 94, 2238-2242).
The important biological role of FAAH suggests a need for molecular regulators of its activity. However, only a select set of FAAH inhibitors have been disclosed. Amongst these is the potent endogenous inhibitor 2-octyl xcex3-bromoacetoacetate, which was discovered prior to FAAH and characterized as an endogenous sleep-inducing compound (M. P. Patricelli, et al., (1998) Bioorg. Med. Chem. Lett. 8, 613-618; and S. Torii, et al., (1973) Psychopharmacologia 29, 65-75). After the discovery of FAAH, elaborations of 2-octyl xcex3-bromoacetoacetate were developed and characterized as potent inhibitors of this enzyme. Moreover, subsequent inhibitors employ a fatty acid structure attached to pharmacophoric head group. The pharmacophoric head groups can generally be classified as either reversible or irreversible. Reversible inhibitors include electrophilic carbonyl moieties, e.g., trifluoromethyl ketones, xcex1-halo ketones, xcex1-keto esters and amides, and aldehydes. Irreversible inhibitors include sulfonyl fluorides and fluorophosphonates. (B. Koutek, et al., (1994) J. Biol. Chem. 269, 22937-22940; J. E. Patterson, et al., (1996) J. Am. Chem. Soc. 118, 5938-5945; D. L. Boger, et al., (1999) Bioorg. Med. Chem. Lett. 9, 167-172; D. G. Deutsch, et al., (1997) Biochem. Pharmacol. 53, 255-260. D. G. Deutsch, et al., (1997) Biochem. Biophys. Res. Commun. 231, 217-221; and L. De Petrocellis, et al., (1997) Biochem. Biophys. Res. Commun. 231, 82-88; and L. De Petrocellis, et al., (1998) In Recent Advances Prostaglandin, Thromboxane, and Leukotriene Research, Plenum Press: New York, 259-263).
One aspect of the invention is directed to an inhibitor of fatty acid amide hydrolase represented by the formula Axe2x80x94Bxe2x80x94C . In this formula, A is an xcex1-keto heterocyclic pharmacophore for inhibiting the fatty acid amide hydrolase; B is a chain for linking A and C, said chain having a linear skeleton of between 3 and 9 atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, the linear skeleton having a first end and a second end, the first end being covalently bonded to the xcex1-keto group of A, with the following proviso: if the first end of said chain is an xcex1-carbon with respect to the xcex1-keto group of A, then the xcex1-carbon is optionally mono- or bis-functionalized with substituents selected from the group consisting of fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl; and C is an activity enhancer for enhancing the inhibition activity of said xcex1-keto heterocyclic pharmacophore, said activity enhancer having at least one xcfx80-unsaturation situated within a xcfx80-bond containing radical selected from a group consisting of aryl, alkenyl, alkynyl, and ring structures having at least one unsaturation, with or without one or more heteroatoms, said activity enhancer being covalently bonded to the second end of the linear skeleton of B, the xcfx80-unsaturation within the xcfx80-bond containing radical being separated from the xcex1-keto group of A by a sequence of no less than 4 and no more than 9 atoms bonded sequentially to one another, inclusive of said linear skeleton.
In a preferred embodiment, said xcex1-keto heterocyclic pharmacophore is represented by the formula: 
In the above formula, xe2x80x9chetxe2x80x9d is selected from the following group: 
In a preferred mode of the above embodiment, xe2x80x9chetxe2x80x9d is selected from the following group: 
One group of inhibitors having a particularly high activity is represented by the following structure: 
In the above structure, R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl; and xe2x80x9cnxe2x80x9d is an integer between 2 and 7.
Another aspect of the invention is directed to a process for inhibiting a fatty acid amide hydrolase. The process employs the step of contacting the fatty acid amide hydrolase with an inhibiting concentration of any of the above inhibitors represented above by the formula Axe2x80x94Bxe2x80x94C.
Another aspect of the invention is directed to a process for enhancing SWS2 or REM sleep. The process employs the step of administering a therapeutically effective quantity to a patient of a fatty acid amide hydrolase inhibitors represented above by formula Axe2x80x94Bxe2x80x94C.